The invention relates to nitrogenous heterocyclic compounds, their preparation and their use as antibacterial medicaments.
The applications WO 02/010172, 02/100860, 04/022563 and 04/052891 describe polycyclic compounds which are useful in combating pathogenic bacteria. The Applicant has discovered novel related compounds, possessing remarkable and completely unexpected antibacterial properties. These compounds possess more particularly an excellent activity on Pseudomonas aeruginosa, a bacterial strain frequently encountered in nosocomial infections as well as in patients suffering from mucoviscidosis. This useful and unexpected activity is not present in the compounds of the applications cited above. It is illustrated hereafter in the experimental part.
Moreover, the compounds of the invention have been shown to be active on animal infection models, including on strains which are usually resistant to the commonly used antibiotics. The compounds of the invention are capable of counteracting the main resistance mechanisms of the bacteria which are the β-lactamases, efflux pumps and porin mutations.
The compounds of the invention correspond to formula (I), in their possible isomeric or diasteroisomeric forms, or mixtures:
in which:    R1 represents a hydrogen atom or a —(CH2)m—NH2; —(CH2)m—NH(C1-C6)alk, —(CH2)m—N(C1-C6)alk2, —(CH2)m—NH—C(NH)NH2 or —(CH2)m—NH—CH═NH radical, in which m is equal to 1 or 2;    R2 and R3 together form a nitrogenous heterocycle of aromatic character with 5 vertices containing 1, 2 or 3 nitrogen atoms, substituted on a nitrogen atom by R4;    R4 represents a hydrogen atom, a (C1-C6)alk radical or a chain of formula:-(A)n-(NH)o—(CH2)p—(CHR′)qR″    A represents a C═O, C═NH or SO2 group;    R′ represents a hydrogen atom or a carboxy group;    R″ represents a hydrogen atom or an NH2, NH(C1-C6)alk, N(C1-C6)alk2, CONH2, CONH(C1-C6)alk, CON(C1-C6)alk2 group, or a saturated heterocycle with 5 or 6 vertices containing 1 or 2 nitrogen atoms and, if appropriate, another heteroatom chosen from oxygen and sulphur, fixed to the chain by a nitrogen atom or by a carbon atom and optionally substituted by a (C1-C6)alk radical;    n, o and q represent 0 or 1 and p represents an integer from 0 to 4;    R5 represents an OSO3H or OCHFCO2H or OCF2CO2H group;it being understood that:            R1 is different from hydrogen, —(CH2)m—NH2, —(CH2)m—NH(C1-C6)alk or —(CH2)m—N(C1-C6)alk2 when R4 is hydrogen, —(C1-C6)alk, —(C═O)n—(CH2)(0-5)—NH2, —(C═O)n—(CH2)(0-5)—NH(C1-C6)alk or —(C═O)n—(CH2)(0-5)—N(C1-C6)alk2 and R5 is an OSO3H group, or when R4 has all of the values of R″ above except for the heterocycle as defined above,        and n, o, p and q cannot all be equal to 0 except when R″ is hydrogen or a CONH2, CONH(C1-C6)alk, CON(C1-C6)alk2 group, or a heterocycle;in the free form and in the form of zwitterions and salts with pharmaceutically acceptable bases and mineral or organic acids.        
By (C1-C6) alkyl radical is meant in particular the methyl, ethyl, propyl or isopropyl radical, as well as linear or branched butyl, pentyl or hexyl;                By heterocycle of aromatic character with 5 vertices containing 1, 2 or 3 nitrogen atoms, is meant those chosen from the list which follows, the two bonds symbolizing the nitrogen-ring junction formed by R2 and R3:        
                By saturated heterocycle with 5 or 6 vertices containing 1 or 2 nitrogen atoms and, if appropriate, an oxygen or sulphur atom, is meant in particular a ring with 5 vertices of pyrrolidine, imidazolidine or pyrazolidine type, or a ring with 6 vertices of piperidine, piperazine, morpholine or thiomorpholine type, the heterocycle being linked to the chain by a nitrogen atom or by a carbon atom.        
Among the acid salts of the products of formula (I), there may be mentioned, among others, those formed with the mineral acids, such as hydrochloric, hydrobromic, hydroiodic, sulphuric or phosphoric acid or with organic acids such as formic, acetic, trifluoroacetic, propionic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, alkanesulphonic acids, such as methanesulphonic and ethanesulphonic acids, arylsuiphonic acids such as benzenesulphonic and paratoluenesulphonic acids. Among the salts of the bases of the products of formula (I) there may be mentioned, among others, those formed with mineral bases such as, for example, sodium, potassium, lithium, calcium, magnesium or ammonium hydroxide or organic bases such as, for example, methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N,N-dimethylethanolamine, tris (hydroxymethyl)aminomethane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine, N-methylglucamine, or also the salts of phosphonium, such as alkylphosphonium, arylphosphoniums, alkylarylphosphonium, alkenylaryiphosphonium or the salts of quaternary ammoniums such as tetra n-butylammonium salt.
The asymmetrical carbon atoms contained in the compounds of formula (I) can independently of one another have the R, S or RS configuration and the compounds of formula (I) are therefore presented in the form of pure enantiomers or pure diastereoisomers or in the form of a mixture of enantiomers in particular of racemates, or mixtures of diastereoisomers. Moreover, the R1 substituent on the one hand and the —C(O)—NR5— chain on the other hand being able to be in cis and/or trans position with respect to the ring to which they are fixed, the compounds of formula (I) are presented in the form of cis isomers or trans isomers or mixtures. Among the compounds of formula (I) as defined above, a subject of the invention is in particular the compounds in which R2 and R3 together form a pyrazolyl heterocycle.
Among the compounds of formula (I) as defined previously, a subject of the invention is in particular those in which R1 represents a —(CH2)m—NH2 radical, as well as those in which R1 represents a —(CH2)m—NH—C(NH)NH2 radical, m in either case being equal to 1. Among the compounds of formula (I), a subject of the invention is also in particular those in which R4 represents a chain of formula -(A)n-(NH)o—(CH2)p—(CHR′)q R″as defined previously, and quite particularly those in which R4 represents a chain of formula —C(O)—NH—(CH2)p—(CHR′)q R″ in which R′, R″, p and q are as defined above. Among the compounds of formula (I), a subject of the invention is also in particular those in which R4 represents a hydrogen atom or a (C1-C6)alk radical and R1 represents a —CH2)m—NH—C(NH)NH2 or —(CH2)m—NH—CH═NH radical, in which m is equal to 1.
Among the compounds of formula (I), a subject of the invention is in particular the compounds described hereafter in the experimental part, in particular those whose names follow:                trans 8-(aminomethyl)-2-(2-amino-ethyl-carbamoyl)-4,8-dihydro-5-(sulphooxy)-4,7-methano-7H-pyrazolo[3,4-e] [1,3] diazepin-6(5H)-one,        trans 8-(aminomethyl)-2-(4-piperazine-1-carbonyl)-4,8-dihydro-5-(sulphooxy)-4,7-methano-7H-pyrazolo[3,4-e] [1,3] diazepin-6(5H)-one,        trans 8-(aminomethyl)-4,8-dihydro-2-(2-dimethylamino-ethyl-carbamoyl)-5-(sulphooxy)-4,7-methano-7H -pyrazolo[3,4-e] [1,3] diazepin-6(5H)-one,        trans 8-(aminomethyl)-2-(3-amino-propyl-carbamoyl)-4,8-dihydro-5-(sulphooxy)-4,7-methano-7H -pyrazolo[3,4-e] [1,3] diazepin-6(5H)-one,        trans 8-(aminomethyl)-2-(carbamoyl-methyl-carbamoyl)-4,8-dihydro-5-(sulphooxy)-4,7-methano-7H-pyrazolo[3,4-e] [1,3] diazepin-6(5H)-one,        trans 8-(aminomethyl)-1-(carbamimidoyl)-4,8-dihydro-5-(sulphooxy)-4,7-methano-7H-pyrazolo[3,4-e] [1,3] diazepin-6(5H)-one,        trans 8-(aminomethyl)-2-(carbamimidoyl)-4,8-dihydro-5-(sulphooxy)-4,7-methano-7H-pyrazolo[3,4-e] [1,3] diazepin-6(5H)-one 8,        trans 8-(amino-methyl)-4,8-dihydro-2-(piperidine-4-carbonyl)-5-(sulphooxy)-4,7-methano-7H-pyrazolo[3,4-e] [1,3] diazepin-6(5H)-one,        trans 8-(amino-methyl)-2-(3-amino-3-carboxy-propyl)-4,8-dihydro-5-(sulphooxy)-4,7-methano-7H-pyrazolo[3,4-e] [1,3] diazepin-6(5H)-one,        trans 8-(guanidino-methyl)-4,8-dihydro-5-(sulphooxy)-4,7-methano-7H-pyrazolo[3,4-e] [1,3] diazepin-6(5H)-one,        trans 8-(guanidino-methyl)-4,8-dihydro-1-methyl-5-(sulphooxy)-4,7-methano-7H-pyrazolo[3,4-e] [1,3] diazepin-6(5H)-one,        trans 8-(guanidino-methyl)-2-carbamoyl-4,8-dihydro-(sulphooxy)-4,7-methano-7H-pyrazolo[3,4-e] [1,3] diazepin-6(5H)-one,        trans 8-(amino-methyl)-4,8-dihydro-1-methyl-5-(carboxy-difluoro-methoxy)-4,7-methano-7H-pyrazolo[3,4-e] [1,3] diazepin-6(5H)-one,        trans 8-(amino-methyl)-2-(amino-carbamoyl)-4,8-dihydro-5-(sulphooxy)-4,7-methano-7H-pyrazolo[3,4-e] [1,3] diazepin-6(5H)-one,in the free form, in the form of zwittterions and salts with pharmaceutically acceptable bases and mineral or organic acids, and in their possible isomeric or diasteroisomeric forms, or mixtures.        
Another subject of the invention is a process for the preparation of the compounds of formula (I), characterized in that a compound of formula (II):
in which R′1, represents an R1 radical in which, if appropriate, the amino function or functions present are protected, R′2 and R′3 together form a nitrogenous heterocycle of aromatic character with 5 vertices containing 1, 2 or 3 nitrogen atoms and P represents a protective group of the hydroxy radical, is treated in the presence of a base, by diphosgene, then by an amine of formula (III):H—NH—(CH2)p—(CHR′a)qR′″  (III)in which R′a and R′″ represent respectively R′ and R″ in which, if appropriate, the reactive carboxy and amino functions are protected, and p and q are as defined above, in order to obtain a compound of formula (IV):
in which R′1 and p are as defined above and R″2 and R″3 together form a nitrogenous heterocycle of aromatic character with 5 vertices containing 1, 2 or 3 nitrogen atoms, substituted on a nitrogen atom by a chain of formula —C(O)—NH—(CH2)p—(CHR′a)q R′″ in which R′a, R′″, p and q are as defined above,    then the radical hydroxy is deprotected and the compound obtained subjected to a sulphation reaction by the action of complexed SO3, or to the action of a reagent of formula Hal-CHF—CO2alk or of formula Hal-CF2—CO2alk, in which Hal represents a halogen atom different from fluorine and alk represents an alkoyl radical containing 1 to 6 carbon atoms, in the presence of a base, then to hydrolysis of the alkoyl ester obtained,    then, if appropriate, the compound obtained is subjected to one or more of the following reactions, in an appropriate order:            deprotection of the amine and, if appropriate, carboxy function or functions present,        salification,        ion exchange,        resolution or separation of diastereoisomers.        
Another subject of the invention is a process for the preparation of compounds of formula (I), characterized in that a compound of formula (II) as defined above is treated with a base, then with a reagent of formula (V):Hal-SO2—NH—(CH2)p—(CHR′a)qR′″  (V)in which Hal represents a halogen atom and R′a, R′″, p and q are as defined above, in order to obtain a compound of formula (IVa):
in which R′1, and P are as defined above and R″2a and R″3a together form a nitrogenous heterocycle of aromatic character with 5 vertices containing 1, 2 or 3 nitrogen atoms, substituted on a nitrogen atom by a chain of formula —SO2—NH—CH2)p—(CHR′a)q R′″ in which R′a, R′″, p and q are as defined above,    then the hydroxy radical is deprotected and the synthesis continued as described above.
Another subject of the invention is a process for the preparation of compounds of formula (I), characterized in that a compound of formula (II) as defined above is treated, if appropriate in the presence of a base, with a reagent of formula (VI):B—C(O)—(NH)o—(CH2)p—(CHR′a)qR′″  (VI)in which B represents an OH radical or a halogen atom and R′a, R′″, o, p and q are as defined above, in order to obtain a compound of formula (IVb):
in which R′1 and P are as defined above and R″2b and R″3b together form a nitrogenous heterocycle of aromatic character with 5 vertices containing 1, 2 or 3 nitrogen atoms, substituted on a nitrogen atom by a chain of formula —C(O)—(NH)o—(CH2)p—(CHR′a)q R′″ in which R′a, R′″, o, p and q are as defined above,    then the synthesis as described above is continued.
Another subject of the invention is a process for the preparation of compounds of formula (I), characterized in that a compound of formula (II) as defined above, is treated in the presence of a base, with a reagent of formula (VII):S═C(NHP′)2  (VII)in which P′ represents a protective group of the amino function, in order to obtain a compound of formula (IVc):
in which R′1 and P are as defined above and R″2c et R″3c together form a nitrogenous heterocycle of aromatic character with 5 vertices containing 1, 2 or 3 nitrogen atoms, substituted on a nitrogen atom by a chain of formula —C(═NH)—NHP′ in which P′ is as defined above,    then the synthesis as described above is continued.
Another subject of the invention is a process for the preparation of compounds of formula (I), characterized in that a compound of formula (II) as defined above is treated by a reagent of formula (VIII):O═C═N—(CH2)p—(CHR′a)qR′″  (VIII)in which R′a, R′″, p and q are as defined above, in order to obtain a compound of formula (IVd)
in which R′1 and P are as defined above and R″2d and R″3d together form a nitrogenous heterocycle of aromatic character with 5 vertices containing 1, 2 or 3 nitrogen atoms, substituted on a nitrogen atom by a chain of formula —(CO)—NH—(CH2)p—(CHR′a)q R′″ in which R′a, R′″, p and q are as defined above, then the synthesis as described above is continued.
A compound of formula (I) in which R4 represents a CO—NH2 or CO—NH(C1-C6)alk group can also be obtained by the action of the compound of formula (II) as defined above, with trimethylsilyl isocyanate or with an isocyanate of formula (C1-C6)alk-N═C═O, in order to obtain a corresponding compound of formula (IV), the synthesis as described above is continued.
Another subject of the invention is a process for the preparation of compounds of formula (I) characterized in that a compound of formula (II):
in which R″2e and R″3e together form a nitrogenous heterocycle of aromatic character with 5 vertices containing 1, 2 or 3 nitrogen atoms optionally substituted by a (C1-C6)alk radical and P is as defined above, is treated by a reagent of formula (IX):CH3—S—C(═NP′)NHP′  (IX)in which P′ is as defined above, in order to obtain a compound of formula (X):
in which R″2e, R″3e, m, P and P′ are as defined above.    then the synthesis as described above is continued.
Prior protection of the amine function at R′1 and in the reagents of formulae III, V, VI, VII, VIII et IX is in particular carried out in the form of benzylated or tritylated derivatives, in the form of carbamates, in particular allyl, benzyl, phenyl or tertbutyl, or also in the form of silylated derivatives such as tertbutyl, dimethyl, trimethyl, triphenyl or also diphenyltertbutyl-silyl, or also phenylsulphonylalkyl or cyanoalkyl derivatives. The deprotection can be carried out by different methods known to a person skilled in the art, depending on the nature of the protective group. It can in particular be carried out by the action of an acid, for example trifluoroacetic acid, the deprotected compound then being obtained in the form of the acid salt. It can also be carried out by hydrogenolysis or using soluble Palladium O complexes or by the action of tetrabutylammonium fluoride or by reduction. An illustration is provided hereafter in the experimental part.
The prior protection of the carboxy at R′a in the reagents of formulae III, V, VI and VIII is in particular carried out in the form of ester type derivatives, in particular alkyl, allyl, benzyl, benzhydryl or p-nitro benzyl. The deprotection can be carried out by different methods known to a person skilled in the art, for example by saponification, acid hydrolysis, hydrogenolysis or cleavage using soluble Palladium O complexes.
The prior protection of the hydroxy of the compound of formula (II) is carried out in a standard fashion, in the form of ethers, esters or carbonates. The ethers can be alkyl or alkoxyalkyl ethers, preferably methyl or methoxyethoxymethyl ethers, aryl or preferably aralkyl ethers, for example benzyl, or silylated ethers, for example the silylated derivatives mentioned above. The esters can be any cleavable ester known to a person skilled in the art and preferably the acetate, propionate or benzoate or p-nitrobenzoate. The carbonates can be for example methyl, tertbutyl, allyl, benzyl or p-nitrobenzyl carbonates The deprotection is carried out by the means known to a person skilled in the art, in particular saponification, hydrogenolysis, cleavage by soluble Palladium O complexes, hydrolysis in acid medium or also, for the silylated derivatives, treatment with tetrabutylammonium fluoride. Illustrations of the above protections and deprotections are provided hereafter in the experimental part.
The base in the presence of which the compound of formula (II) is reacted and the diphosgene can for example be an amine such as triethylamine, but other bases known to a person skilled in the art for reactions of this type can be used. It is possible to operate in a solvent such as methylene chloride. The sulphation reaction is carried out by the action of SO3 complexes such as SO3-pyridine or SO3-dimethylformamide, by operating in pyridine or in dimethylformamide, the salt formed, for example the pyridine salt, then being able to be exchanged for example for a salt of another amine, quaternary ammonium or alkali metal. An illustration is provided in the experimental part.
The salification by acids is if appropriate carried out by adding an acid in soluble phase to the compound. The salification by bases of the sulphooxy function can be carried out from the salt of the amine and in particular pyridine obtained during the action of the SO3-amine complex and the other salts are obtained from this amine salt. It is possible in particular to operate by ion exchange resin. The separation of the enantiomers and diastereoisomers can be carried out according to the techniques known to a person skilled in the art, in particular, chiral or non-chiral phase chromatography. Examples of conditions which can be used are also described in the application WO 04/052891 or also in the application WO 02/100860. The base in the presence of which the compound of formula (II) is reacted prior to the action of the reagent of formula (V) can for example be an alkaline hydride such as sodium hydride, but other bases known to a person skilled in the art for reactions of this type can be used. The reaction can be carried out in tetrahydrofuran. The base in the presence of which the compound of formula (II) is reacted with the reagent of formula (VI) in which B represents a halogen can for example be an amine such as diisopropylethylamine or triethylamine. The operation can be carried out in dimethylformamide or dichloromethane.
The conditions under which the compound of formula (II) is reacted with the reagent of formula (VI) in which B represents an OH, are the standard conditions for peptide couplings known to a person skilled in the art. Such conditions are illustrated hereafter in the experimental part. The base in the presence of which the compound of formula (II) and the reagent of formula (VII) are reacted can for example be an amine such as triethylamine, but other bases known to a person skilled in the art for reactions of this type can be used. The operation is carried out in the presence of mercury chloride and in a solvent such as methylene chloride.
The reaction of the compound of formula (II) with the reagent of formula (VIII) can be carried out in acetonitrile or a mixture with tetrahydrofuran. The reaction of the compound of formula (II′) with the reagent of formula (IX) is carried out in the presence of trimethylphosphine and the operation is carried out for example in tetrahydrofuran or a tetrahydrofuran/toluene mixture. A subject of the invention is also the intermediate compounds of formulae (IV), (IVa), (IVb), (IVc), (IVd) and (X) as defined above. The compounds of formula (II) and (II′) can be obtained by processes described in the applications WO 02/100860 or 04/052891.
As indicated above, the compounds of general formula (I) possess an excellent antibiotic activity on Pseudomonas aeruginosa as well as on animal infection models by strains resistant to the antibacterial agents commonly used. This remarkable and unexpected antibiotic activity had not been observed for the compounds described in the application WO 04/052891 and in particular for structurally similar compounds. This is illustrated hereafter.
These properties make said compounds, in the free form and in the form of zwitterions or pharmaceutically acceptable salts of acids and o bases, to be used as medicaments in the treatment of severe Pseudomonas infections, in particular nosocomial infections and, generally, major infections in patients at risk. They may in particular be infections of the airways, for example acute pneumonia or chronic infections of the lower airways, infections of the blood, for example the septicaemia, acute or chronic infections of the urinary tract, those of the auditory system, for example malignant external otitis, or chronic suppurative otitis, those of the skin and the soft tissues, for example dermatitis, infected wounds, folliculitis, pyodermatitis, resistant forms of acne, eye infections, for example corneal ulcer, those of the nervous system, in particular meningitis and cerebral abscess, cardiac infections such as endocarditis, bone and joint infections such as stenoarticular pyoarthrosis, vertebral osteomyelitis, pubic symphysitis, infections of the gastro-intestinal tract, such as necrotizing enterocolitis and perirectal infections.
A subject of the present invention is therefore also, as medicaments and in particular antibiotic medicaments, the compounds of formula (I) as defined above, in the free form and in the form of zwitterions and salts with pharmaceutically acceptable bases and mineral or organic acids. Among the compounds of formula (I), a subject of the invention is in particular, as medicaments, the compounds in which R2 and R3 together form a substituted pyrazolyl heterocycle. Among the compounds of formula (I), a more particular subject of the invention is, as medicaments, those in which R1 represents a —(CH2)m—NH2 radical, as well as those in which R1 represents a —(CH2)m—NH—C(NH)NH2 radical, m in either case being equal to 1. Among the compounds of formula (I), a subject of the invention is also in particular, as medicaments, those in which R4 represents a chain of formula -(A)n-(NH)o—(CH2)p—(CHR′)q R″ as defined previously and quite particularly those in which R4 represents a chain of formula —C(O)—NH—(CH2)p—(CHR′)q R″ in which R′, R″, p and q are as defined above. Among the compounds of formula (I), a subject of the invention is also in particular, as medicaments, those in which R4 represents a hydrogen atom or a (C1-C6)alk radical and R1 represents a —(CH2)m—NH—C(NH)NH2 or —(CH2)m—NH—CH═NH radical, in which m is equal to 1.
Among the compounds of formula (I), a subject of the invention is quite particularly, as medicaments, the compounds described hereafter in the experimental part and in particular those the names of which follow:                trans 8-(aminomethyl)-2-(2-amino-ethyl-carbamoyl)-4,8-dihydro-5-(sulphooxy)-4,7-methano-7H-pyrazolo[3,4-e] [1,3] diazepin-6(5H)-one,        trans 8-(aminomethyl)-2-(4-piperazine-1-carbonyl)-4,8-dihydro-5-(sulphooxy)-4,7-methano-7H-pyrazolo[3,4-e] [1,3] diazepin-6(5H)-one,        trans 8-(aminomethyl)-4,8-dihydro-2-(2-dimethylamino-ethyl-carbamoyl)-5-(sulphooxy)-4,7-methano-7H-pyrazolo[3,4-e] [1,3] diazepin-6(5H)-one,        trans 8-(aminomethyl)-2-(3-amino-propyl-carbamoyl)-4,8-dihydro-5-(sulphooxy)-4,7-methano-7H-pyrazolo[3,4-e] [1,3] diazepin-6(5H)-one,        trans 8-(aminomethyl)-2-(carbamoylmethyl-carbamoyl)-4,8-dihydro-5-(sulphooxy)-4,7-methano-7H-pyrazolo[3,4-e] [1,3] diazepin-6(5H)-one,        trans 8-(aminomethyl)-1-(carbamimidoyl)-4,8-dihydro-5-(sulphooxy)-4,7-methano-7H-pyrazolo[3,4-e] [1,3] diazepin-6(5H)-one,        trans 8-(aminomethyl)-2-(carbamimidoyl)-4,8-dihydro-5-(sulphooxy)-4,7-methano-7H-pyrazolo[3,4-e] [1,3] diazepin-6(5H)-one,        trans 8-(amino-methyl)-4,8-di hydro-2-(piperidine-4-carbonyl)-5-(sulphooxy)-4,7-methano-7H-pyrazolo[3,4-e] [1,3] diazepin-6(5H)-one,        trans 8-(amino-methyl)-2-(3-amino-3-carboxy-propyl)-4,8-dihydro-5-(sulphooxy)-4,7-methano-7H-pyrazolo[3,4-e] [1,3] diazepin-6(5H)-one,        trans 8-(guanidino-methyl)-4,8-dihydro-5-(sulphooxy)-4,7-methano-7H-pyrazolo[3,4-e] [1,3] diazepin-6(5H)-one,        trans 8-(guanidino-methyl)-4,8-dihydro-1-methyl-5-(sulphooxy)-4,7-methano-7H-pyrazolo[3,4-e] [1,3] diazepin-6(5H)-one,        trans 8-(guanidino-methyl)-2-carbamoyl-4,8-dihydro-5-(sulphooxy)-4,7-methano-7H-pyrazolo[3,4-e] [1,3] diazepin-6(5H)-one,        trans 8-(amino-methyl)-4,8-dihydro-1-methyl-5-(carboxy-difluoro-methoxy)-4,7-methano-7H-pyrazolo[3,4-e] [1,3] diazepin-6(5H)-one,        trans 8-(amino-methyl)-2-(amino-carbamoyl)-4,8-dihydro-5-(sulphooxy)-4,7-methano-7H-pyrazolo[3,4-e] [1,3] diazepin-6(5H)-one,in the free form, in the form of zwittterions and salts with pharmaceutically acceptable bases and mineral or organic acids, in their possible isomeric or diasteroisomeric forms, or mixtures.        
A subject of the invention is also the pharmaceutical compositions containing, as active ingredient, at least one of the compounds according to the invention as defined above. These compositions can be administered by buccal, rectal, parenteral route, in particular intramuscular, or by local route as a topical application on the skin and mucous membranes. The compositions according to the invention can be solid or liquid and be presented in the pharmaceutical forms commonly used in human medicine, such as for example, plain or sugar-coated tablets, gelatin capsules, granules, suppositories, injectable preparations, ointments, creams, gels; they are prepared according to the usual methods. The active ingredient or ingredients can be incorporated with excipients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents, preservatives. These compositions can also be presented in the form of a lyophilisate intended to be dissolved extemporaneously in an appropriate vehicle for example apyrogenic sterile water.
The dose administered varies according to the condition treated, the patient in question, the administration route and the product considered. It can, for example, be comprised between 0.250 g and 10 g per day, by oral route in adults, with the product described in Example 1, 4 or 5 or also comprised between 0.25 g and 5 g per day by intramuscular or intravenous route. The products of formula (I) can also be used such as disinfectants for surgical instruments.